Oral sustained-release formulation is developed to control the release of active ingredient at a designed rate and to obtain its optimal blood concentration therapeutically. This property leads to the reduction of the administration frequency, which helps to increase patient compliance and prevent adverse effects.
In order to achieve the object, a variety of dosage forms have been developed. Among them, because of simple composition and ease of manufacture, many studies have been conducted on a matrix system, in which active ingredients are dispersed in polymers which control the release rate
However, the release from the simple matrix containing water-soluble polymers such as hydroxypropylmethylcellulose is subject to Fickian diffusion, which causes some drawbacks such as an initial burst.
There have been attempts to introduce an additional release-controlling layer into the matrix formulation, for the purpose of avoiding an initial burst and initiating the release of active ingredient after a predetermined time.
U.S. Pat. No. 5,422,123 discloses a tablet consisting of a core and a support applied to the core to partly cover its surface, in which the release of pharmaceutically active ingredient is controlled as follows: The core contains the drug and a polymer which swells and gelates upon contact with aqueous media in a ratio of 1:9 to 9:1, based on the amount of drug, so that the release of pharmaceutically active ingredient is controlled by the same mechanism as in the matrix formulation, but the support containing a polymer which is slowly soluble or gellable in aqueous media controls the surface area of the core and varies the release patterns.
U.S. Pat. No. 5,549,913 discloses a multilayer tablet for release of pharmaceutically active ingredient at a constant rate with a zero order kinetic profile, in which two outer layers contain pharmaceutically active ingredient and hydrophilic polymers, and an inner layer contains a water-soluble polymer without the pharmaceutically active ingredient. The inner layer is readily dissolved in aqueous media to separate the two outer layers, and thus to increase the surface area of the matrix.
U.S. Pat. No. 5,626,874 discloses a multilayer tablet consisting of two outer layers containing gellable or erodible polymers and an inner layer containing an active ingredient. The side surface of the inner layer occupies about 5 to 35% of the tablet's total surface.
U.S. Pat. No. 5,783,212 discloses a multilayer tablet for release of pharmaceutically active ingredient at a constant rate with a zero order kinetic profile, in which two outer layers contain swellable and erodible polymers, an inner layer contains a pharmaceutically active ingredient and swellable and erodible polymers, and each layer differs in composition and thickness.
U.S. Pat. No. 6,730,321 discloses a press-coated tablet that facilitates a pulsatile release of pharmaceutically active ingredient, consisting of an immediate-release core and a sustained-release layer, which is press-coated.
In the above prior arts, an immediate-release inner layer containing pharmaceutically active ingredient is not introduced or, even if introduced, the immediate-release inner layer is completely coated with the controlling layers. This is because if the inner layer of the triple layer tablet does not contain polymers to control the release and is exposed to aqueous media, there will be several problems; namely, excessive initial burst, layer separation due to loss of the inner immediate-release layer, and significant deviation in release rate, which can be fully predicted by those skilled in the art.
The present inventors have found that surprisingly although an inner immediate-release layer containing a pharmaceutically active ingredient is not completely coated but contacted with two outer layers, if said layers contain swellable polymers, those two outer layers swell to form gelled layers surrounding the lateral side of the inner layer rapidly upon exposure to aqueous media acting to control the release of active ingredient from the inner immediate-release layer uniformly and reproducibly, thereby completing the present invention.